Abstract

BACKGROUND:

Lysosomal storage disorders (LSDs), are a heterogeneous group of rare disorders caused by defects in genes encoding for proteins involved in the lysosomal degradation of macromolecules. They occur at a frequency of about 1 in 5,000 live births, though recent neonatal screening suggests a higher incidence. New treatment options for LSDs demand a rapid, early diagnosis of LSDs if maximal clinical benefit is to be achieved.

RESULTS:

With a sensitivity of 100.0% and specificity of 91.0% a cut-off of 1.4 ng/ml was established. Comparison with cholestane-3β,5α,6β-triol and relative acidic compartment volume measurements were carried out with a subset of 125 subjects. Both cholestane-3β,5α,6β-triol and lyso-Sphingomyelin-509 were sufficient in establishing the diagnosis of NPC1 and correlated with disease severity.

CONCLUSION:

In summary, we have established a new biomarker for the diagnosis of NPC1, and further studies will be conducted to assess correlation to disease progress and monitoring treatment.

Chemical structure of Lyso-Sphingomyelin-509. This substance was analysed by HPLC-MS/MS with high sensitivity and specificity of diagnosing NPC. The precise structure of lyso-SM-509 has not yet been elucidated.

Levels of lyso-SM-509 in patients with NPC1 (n = 110), NP-A/B (n = 21), as well as healthy controls (n = 43) and NPC1 carriers (n = 63) and NP-A/B carriers (n = 5). (A) Lyso-SM-509 allows distinguishing between healthy controls and patients with NPC1. Notably, the biomarker levels are for NP-A/B patients were 3.55-times higher (29.4 ng/ml (IQR: 14.8-40.0). Notably, only in two cases lyso-SM-509 levels above 2.5 ng/ml can be detected in a carrier of a NPC1 mutation and in none of the healthy controls. (B) Levels of lyso-SM-509 in NPC1 by age. Note that Lyso-SM-509 is higher in younger NPC1 patients (ρ = -0.519, p < 0.001), reflecting the severity of early onset disease as shown by Te Vruchte and colleagues (11).

Comparison of Lyso-SM-509, cholestane-3β,5α,6β-triol and MEFL. (A) Boxplot of lyso-SM-509 by genotype, (B) boxplot of cholestane-3β,5α,6β-triol by genotype, (C) boxplot of MEFL (LysoTracker) by genotype. Both lyso-SM-509 and cholestane-3β,5α,6β-triol facilitate the distinction of NPC patients from healthy controls.